T-cell acute lymphoblastic leukemia (T-ALL) comprises −20% of ALL (Kersey J H., Blood 1997; 90: 4243-4251), with ALL being the most common type of cancer in children. A better understanding of the biology of T-ALL at the molecular level would facilitate the development of selective therapy that exploits specific biological properties of the leukemia, thereby improving the outlook for this disease. Even though a number of leukemia cell lines of T-cell origin have been established from patients (Gjerset R, et al., Cancer Res 1990; 50: 10-14; Smith S D, et al., Blood 1978; 52: 712-718; Lange B, et al., Blood 1987; 70: 192-199; and Smith S D, et al., Cancer Res 1984; 44: 5657-5660), difficulty in maintaining primary cultures of leukemia cells from patients has impeded study of the development of the disease.
Leukemic progenitor cells have been implicated in the maintenance and expansion of leukemic blast populations (Uckun F M, et al., Immunology 1988; 140: 2103-2111; Uckun F M, et al., Blood 1990; 76: 1723-1733). These clonogenic blast cells comprise only 0.05 to 1.5% of the bulk marrow or peripheral blood blasts from ALL patients (Uckun F M, et al., Immunology 1988; 140: 2103-2111; Touw I, et al., Blood 1986; 68: 1088-1094), identified on the basis of their ability to proliferate and form colonies in semi-solid media in response to specific growth factors (Touw I, et al., Blood 1986; 68: 1088-1094; Touw I, et al., Blood 1985; 66: 556-561). It is generally assumed that the colony-forming blasts represent the in vitro counterparts of the in vivo ALL blast progenitors (Uckun F M, et al., Immunology 1988; 140: 2103-2111). Despite these in vitro studies, leukemia-initiating cells were not demonstrated in vivo until recently (Holyoake T, et al., Blood 1999; 94: 2056-2064; Ailles LE, et al., Nat Med 1997; 3: 730-737; and Terpstra W, et al., Blood 1996; 87: 2187-2194).
The ability to engraft T-ALL cells directly from patient samples into immunodeficient rodents such as Nonobese Diabetic x Severe Combined Immunodeficient (NOD/scid) mice would be uniquely valuable in this regard, as well as for predicting the clinical course of the disease, detecting residual disease, and developing individualized therapeutic strategies. The availability of a robust in vivo mouse model for T-ALL would expedite characterization of the corresponding leukemia-initiating cell, as well as delineation of cellular hierarchy within the leukemia. Pre-conditioning sub-lethally irradiated immunodeficient NOD/scid mice with human cord blood mononuclear cells (MNCs) facilitates the subsequent engraftment in these mice of primary T-ALL cells obtained from patients at the time of diagnosis. The present invention provides, in great detail a novel in vivo model of human leukemia engraftment. The data show that the level of engraftment depends on both the number of cord blood MNCs and T-ALL cells injected. In addition, the data document the fidelity of the model to the human pathology with regard to the pattern of leukemia dissemination, as well as with regard to the maintenance of the leukemia-initiating cell within the leukemia-engrafted mouse. The data also provide evidence that the cord blood pre-conditioned NOD/scid mouse is applicable to the study of other human leukemias in addition to T-ALL.